Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis
- PMID: 39196111
- PMCID: PMC11358008
- DOI: 10.1038/s44161-024-00432-0
Bone morphogenic protein-4 availability in the cardiac microenvironment controls inflammation and fibrosis in autoimmune myocarditis
Abstract
Myocarditis is an inflammatory heart disease that leads to loss of cardiomyocytes and frequently precipitates fibrotic remodeling of the myocardium, culminating in heart failure. However, the molecular mechanisms underlying immune cell control and maintenance of tissue integrity in the inflamed cardiac microenvironment remain elusive. In this study, we found that bone morphogenic protein-4 (BMP4) gradients maintain cardiac tissue homeostasis by single-cell transcriptomics analyses of inflamed murine and human myocardial tissues. Cardiac BMP pathway dysregulation was reflected by reduced BMP4 serum concentration in patients with myocarditis. Restoration of BMP signaling by antibody-mediated neutralization of the BMP inhibitors gremlin-1 and gremlin-2 ameliorated T cell-induced myocardial inflammation in mice. Moreover, progression to inflammatory cardiomyopathy was blocked through the reduction of fibrotic remodeling and preservation of cardiomyocyte integrity. These results unveil the BMP4-gremlin axis as a druggable pathway for the treatment of myocardial inflammation, limiting the severe sequelae of cardiac fibrosis and heart failure.
© 2024. The Author(s).
Conflict of interest statement
C.P.-S., C.G.-C., H.-W.C., L.O. and B.L. are founders and C.P.-S., C.G.-C., H.-W.C., L.O., L.T.C. and B.L. are shareholders of Stromal Therapeutics. L.T.C., L.O. and B.L. are members of the board of Stromal Therapeutics. C.P.-S., C.G.-C., L.O. and B.L. are listed as inventors on patent WO 2022/084400 A1. All other authors declare no competing interests.
Figures













References
-
- Caforio, A. L. et al. Current state of knowledge on aetiology, diagnosis, management, and therapy of myocarditis: a position statement of the European Society of Cardiology Working Group on Myocardial and Pericardial Diseases. Eur. Heart J.34, 2636–2648 (2013). 10.1093/eurheartj/eht210 - DOI - PubMed
Publication types
MeSH terms
Substances
Grants and funding
- 182583/Schweizerischer Nationalfonds zur Förderung der Wissenschaftlichen Forschung (Swiss National Science Foundation)
- 101019872/EC | EU Framework Programme for Research and Innovation H2020 | H2020 Priority Excellent Science | H2020 European Research Council (H2020 Excellent Science - European Research Council)
- FF21055/Schweizerische Herzstiftung (Swiss Heart Foundation)
LinkOut - more resources
Full Text Sources
Medical
Molecular Biology Databases